It is a common opinion that metabotropic glutamate receptor subtype 6 (mGluR6) is expressed exclusively in the retina, and in particular in the dendrites of ON-bipolar cells. Glutamate released in ...darkness from photoreceptors activates mGluR6, which is negatively associated with a membrane non-selective cation channel, the transient receptor potential melanoma-related 1, TRPM1, resulting in cell hyperpolarization. The evidence that mGluR6 is expressed not only in the retina but also in other tissues and cell populations has accumulated over time. The expression of mGluR6 has been identified in microglia, bone marrow stromal and prostate cancer cells, B lymphocytes, melanocytes and keratinocytes and non-neural tissues such as testis, kidney, cornea, conjunctiva, and eyelid. The receptor also appears to be expressed in brain areas, such as the hypothalamus, cortex, hippocampus, nucleus of tractus solitarius, superior colliculus, axons of the corpus callosum and accessory olfactory bulb. The pharmacological activation of mGluR6 in the hippocampus produced an anxiolytic-like effect and in the periaqueductal gray analgesic potential. This review aims to collect all the evidence on the expression and functioning of mGluR6 outside the retina that has been accumulated over the years for a broader view of the potential of the receptor whose retinal confinement appears understimated.
Background and purpose:
N‐arachidonoyl‐serotonin (AA‐5‐HT) is an inhibitor of fatty acid amide hydrolase (FAAH)‐catalysed hydrolysis of the endocannabinoid/ endovanilloid compound, anandamide (AEA). ...We investigated if AA‐5‐HT antagonizes the transient receptor potential vanilloid‐1 (TRPV1) channel and, as FAAH and TRPV1 are targets for analgesic compounds, if it exerts analgesia in rodent models of hyperalgesia.
Experimental approach:
AA‐5‐HT was tested in vitro, on HEK‐293 cells overexpressing the human or the rat recombinant TRPV1 receptor, and in vivo, in rats and mice treated with formalin and in rats with chronic constriction injury of the sciatic nerve. The levels of the endocannabinoids, AEA and 2‐arachidonoylglycerol, in supraspinal (periaqueductal grey, rostral ventromedial medulla), spinal or peripheral (skin) tissues were measured.
Key results:
AA‐5‐HT behaved as an antagonist at both rat and human TRPV1 receptors (IC50=37‐40 nM against 100 nM capsaicin). It exerted strong analgesic activity in all pain models used here. This activity was partly due to FAAH inhibition, elevation of AEA tissue levels and indirect activation of cannabinoid CB1 receptors, as it was reversed by AM251, a CB1 antagonist. AA‐5‐HT also appeared to act either via activation/desensitization of TRPV1, following elevation of AEA, or as a direct TRPV1 antagonist, as suggested by the fact that its effects were either reversed by capsazepine and 5′‐iodo‐resiniferatoxin, two TRPV1 antagonists, or mimicked by these compounds administered alone.
Conclusions and implications:
Possibly due to its dual activity as a FAAH inhibitor and TRPV1 antagonist, AA‐5‐HT was highly effective against both acute and chronic peripheral pain.
British Journal of Pharmacology (2007) 150, 766–781. doi:10.1038/sj.bjp.0707145
Several studies have suggested that obesity could have a negative effect on response to anti-tumor necrosis factor α (anti-TNFα) in rheumatoid arthritis (RA). Little is known about the impact of body ...mass index (BMI) on other biologic agents. We aimed to evaluate the effect of BMI on response to tocilizumab (TCZ) in RA. RA patients treated with TCZ were included in this multicenter retrospective study. BMI was calculated at the initiation of treatment. After 6 months of treatment, change from baseline in DAS28, pain on a visual analog scale, erythrocyte sedimentation rate and C-reactive protein level, and tender and swollen joints were analyzed. The primary endpoint was decrease in DAS28 ≥ 1.2. Secondary outcomes were good response and remission by EULAR criteria. At baseline, among 115 RA patients included, the median (interquartile range) BMI was 25.4 (22.0–28.8) kg/m
2
. The number of patients with normal weight, overweight, and obesity was 53 (46 %), 37 (32 %), and 25 (22 %), respectively. Baseline characteristics did not differ between the three subgroups of BMI. The median BMI did not differ between responders and non-responders for DAS28 decrease ≥1.2 (25.7 22.1–29.9 vs 24.9 22.0–27.1,
P
= 0.38), EULAR good response (25.9 22.8–30.0 vs 25.4 22.0–28.4,
P
= 0.61), and remission (25.1 22.5–28.6 vs 25.4 22.0–28.9,
P
= 0.76). BMI did not affect the response to TCZ in RA. If confirmed, these results could be helpful for the selection of a biologic agent in obese RA patients.
In the ventrolateral periaqueductal gray (PAG), activation of excitatory output neurons projecting monosynaptically to OFF cells in the rostral ventromedial medulla (RVM) causes antinociceptive ...responses and is under the control of cannabinoid receptor type-1 (CB1) and vanilloid transient receptor potential vanilloid type 1 (TRPV1) receptors. We studied in healthy rats the effect of elevation of PAG endocannabinoid anandamide and 2-arachidonoylglycerol (2-AG) levels produced by intra-PAG injections of the inhibitor of fatty acid amide hydrolase URB597 cyclohexylcarbamic acid-3'-carbamoyl-biphenyl-3-yl ester on 1) nociception in the "plantar test" and 2) spontaneous and tail-flick-related activities of RVM neurons. Depending on the dose or time elapsed since administration, URB597 (0.5-2.5 nmol/rat) either suppressed or increased thermal nociception via TRPV1 or CB1 receptors, respectively. TRPV1 or cannabinoid receptor agonists capsaicin (6 nmol) and (R)-(+)-2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo1,2,3,-de-1,4-benzoxazin-6-yl-1-naphthalenylmethanone mesylate WIN55,212-2 (4 nmol) also suppressed or enhanced nociception, respectively. URB597 dose dependently enhanced PAG anandamide and 2-AG levels, with probable subsequent activation of TRPV1/CB1 receptors and only CB1 receptors, respectively. The TRPV1-mediated antinociception and CB1-mediated nociception caused by URB597 correlated with enhanced or reduced activity of RVM OFF cells, suggesting that these effects occur via stimulation or inhibition of excitatory PAG output neurons, respectively. Accordingly, several ventrolateral PAG neurons were found by immunohistochemistry to coexpress TRPV1 and CB1 receptors. Finally, at the highest doses tested, URB597 (4 nmol/rat) and, as previously reported, WIN55,212-2 (25-100 nmol) also caused CB(1)-mediated analgesia, correlating with stimulation (possibly disinhibition) of RVM OFF cells. Thus, endocannabinoids affect the descending pathways of pain control by acting at either CB1 or TRPV1 receptors in healthy rats.
Periodic repetition of right heart catheterization (RHC) in pulmonary arterial hypertension (PAH) can be challenging. We evaluated the correlation between RHC and cardiopulmonary exercise test (CPET) ...aiming at CPET use as a potential noninvasive tool for hemodynamic burden evaluation. One hundred and forty‐four retrospective PAH patients who had performed CPET and RHC within 2 months were enrolled. The following analyses were performed: (a) CPET parameters in hemodynamic variables tertiles; (b) position of hemodynamic parameters in the peak end‐tidal carbon dioxide pressure (PETCO2) versus ventilation/carbon dioxide output (VE/VCO2) slope scatterplot, which is a specific hallmark of exercise respiratory abnormalities in PAH; (c) association between CPET and a hemodynamic burden score developed including mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), cardiac index, and right atrial pressure. VE/VCO2 slope and peak PETCO2 significantly varied in mPAP and PVR tertiles, while peak oxygen uptake (peak VO2) and O2 pulse varied in the tertiles of all hemodynamic parameters. PETCO2 versus VE/VCO2 slope showed a strong hyperbolic relationship (R2 = 0.7627). Patients with peak PETCO2 > median (26 mmHg) and VE/VCO2 slope < median (44) presented lower mPAP and PVR (p < 0.005) than patients with peak PETCO2 < median and VE/VCO2 slope > median. Multivariate analysis individuated peak VO2 (p = 0.0158) and peak PETCO2 (p = 0.0089) as hemodynamic score independent predictors; the formula 11.584 − 0.0925 × peak VO2 − 0.0811 × peak PETCO2 best predicts the hemodynamic score value from CPET data. A significant correlation was found between estimated and calculated scores (p < 0.0001), with a precise match for patients with mild‐to‐moderate hemodynamic burden (76% of cases). The results of the present study suggest that CPET could allow to estimate the hemodynamic burden in PAH patients.
p75 neurotrophin receptor (p75NTR) belongs to the TNF-receptor superfamily and signals apoptosis in many cell settings. In human epidermis, p75NTR is mostly confined to the transit-amplifying (TA) ...sub-population of basal keratinocytes. Brain-derived neurotrophic factor (BDNF) or neurotrophin-4 (NT-4), which signals through p75NTR, induces keratinocyte apoptosis, whereas β-amyloid, a ligand for p75NTR, triggers caspase-3 activation to a greater extent in p75NTR transfected cells. Moreover, p75NTR co-immunoprecipitates with NRAGE, induces the phosphorylation of c-Jun N-terminal kinase (JNK) and reduces nuclear factor kappa B (NF-κB) DNA-binding activity. p75NTR also mediates pro-NGF-induced keratinocyte apoptosis through its co-receptor sortilin. Furthermore, BDNF or β-amyloid cause cell death in TA, but not in keratinocyte stem cells (KSCs) or in p75NTR silenced TA cells. p75NTR is absent in lesional psoriatic skin and p75NTR levels are significantly lower in psoriatic than in normal TA keratinocytes. The rate of apoptosis in psoriatic TA cells is significantly lower than in normal TA cells. BDNF or β-amyloid fail to induce apoptosis in psoriatic TA cells, and p75NTR retroviral infection restores BDNF- or β-amyloid-induced apoptosis in psoriatic keratinocytes. These results demonstrate that p75NTR has a pro-apoptotic role in keratinocytes and is involved in the maintenance of epidermal homeostasis.
Abstract Neuropathic pain is a devastating neurological disease that seriously affects quality of life in patients. The mechanisms leading to the development and maintenance of neuropathic pain are ...still poorly understood. However, recent evidence points towards a role of spinal microglia in the modulation of neuronal mechanisms. In this context, cannabinoids are thought to modulate synaptic plasticity as well as glial functions. Here, we have investigated the effect of chronic treatment with a selective agonist of cannabinoid type 2 receptor (CB2), 1-(2′,4′-dichlorophenyl)-6-methyl- N -cyclohexylamine-1,4-dihydroindeno1,2-cpyrazole-3 carboxamide (NESS400), on pain thresholds in the spared nerve injury (SNI) model in the mouse and on the distribution and activation of spinal microglia. Repeated treatment with NESS400 (4 mg/kg) significantly alleviated neuropathic mechanical allodynia and thermal hyperalgesia. In the dorsal horn (L4–L6) of neuropathic mice microglia activation (quantification of the length of microglial processes) and astrocytosis were associated with CB2 receptor over-expression on both cell types. Treatment with NESS400 significantly reduced the number of hypertrophic microglia while leaving microglial cell number unaffected and reduced astrogliosis. Moreover, prolonged administration of NESS400 reduced mRNA expression of pro-inflammatory markers and enhanced anti-inflammatory marker gene expression in dorsal horn extracts. In conclusion, we show that selective CB2 receptor stimulation prevents thermal hyperalgesia, alleviates mechanical allodynia and facilitates the proliferation of anti-inflammatory microglial phenotype in the ipsilateral dorsal horn of the spinal cord in SNI mice.
Epidermal homeostasis depends on the coordinated control of keratinocyte cell cycle. Differentiation and the alteration of this balance can result in neoplastic development. Here we report on a novel ...DLX3-dependent network that constrains epidermal hyperplasia and squamous tumorigenesis. By integrating genetic and transcriptomic approaches, we demonstrate that DLX3 operates through a p53-regulated network. DLX3 and p53 physically interact on the p21 promoter to enhance p21 expression. Elevating DLX3 in keratinocytes produces a G1-S blockade associated with p53 signature transcriptional profiles. In contrast, DLX3 loss promotes a mitogenic phenotype associated with constitutive activation of ERK. DLX3 expression is lost in human skin cancers and is extinguished during progression of experimentally induced mouse squamous cell carcinoma (SCC). Reinstatement of DLX3 function is sufficient to attenuate the migration of SCC cells, leading to decreased wound closure. Our data establish the DLX3-p53 interplay as a major regulatory axis in epidermal differentiation and suggest that DLX3 is a modulator of skin carcinogenesis.
Background and Aims
These last years, minor cultivars have gained attention as they provide an opportunity to offer original products in a global market and to combat global warming. Recent evidence ...brought to light the existing diversity within the group of autochthonous cultivars from Argentina and other South American countries, commonly known as criollas. The objective was to prospect, rescue and identify grapevine phenotypes recovered in ancient vineyards as putative criollas, in the western provinces of Argentina.
Methods and Results
We collected 60 samples in 11 locations. Their identity and pedigree were analysed through nuclear simple sequence repeat (nSSR) markers. The 60 samples were grouped in 45 different genotypes, 19 of them corresponding to previously registered cultivars, while 26 were new genotypes, with no correspondence in international databases. The majority (18) of the 26 new genotypes were related with the criollas group while other genotypes presented a totally different genetic profile and its origin remains to be elucidated.
Conclusions
The diversity within the South American cultivars is higher than previously thought. Ancient vineyards, located in isolated valleys, are reservoirs of minor cultivars, and growers have played a key role in maintaining and conserving them.
Significance of the Study
This genetic diversity constitutes a valuable tool to explore alternatives for diversification and adaptation to climate change.
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